Phase 1 study of ADG126, a novel masked anti-CTLA-4 SAFEbody, that combines tumor-localized activation with strong T<sub>reg</sub> depletion and soft ligand blocking in patients with advanced solid tumors.
Authors: Gary Edward Richardson, Anthony W. Tolcher, Michelle Frances Morris, Paul L. de Souza, Anis Hamid, Xiaohong She, Lvyu Zhu, Hongyan Wang, Songmao Zheng, Guizhong Liu, Yan Li, Fangyong Felix Du, Steven Fischkoff, Hua Gong, Jiping Zha, Peter Luo
Journal: Journal of Clinical Oncology (2022)

e17601 Background: SAFEbody ADG126, a masked version of NEObody ADG116 (ESMO IO Conference Abstract #394, NCT04501276), targets a unique species-conserved CTLA-4 epitope with preclinical safety and efficacy profiles superior to ipilimumab, an approved anti-CTLA-4 immune checkpoint inhibitor known to cause treatment-related irAEs in ̃70% of patients. ADG126 is designed to unlock the great potential of anti-CTLA-4 immunotherapy in 4 key ways: 1) improving safety through masking to limit on-target off-tumor irAEs in normal tissues, 2) widening the therapeutic window through selective activation in tumor microenvironment (TME), 3) maximizing anti-tumorigenic effects through prolonged exposure and steady accumulation of activated ADG126 in TME, 4) enhancing antitumor potency relative to ipilimumab via a higher T eff /T reg ratio achieved by combining T cell activation and strong ADCC-mediated T reg depletion in TME. We present interim results from our ongoing Phase 1 study of ADG126 (NCT04645069). Methods: ADG126 monotherapy [0.1, 0.3, 1, 3, 10 mg/kg (mpk)] was given to patients with advanced solid tumors Q3W IV. Primary endpoints are safety and tolerability. Secondary endpoints are PK, ORR per RECIST v1.1, and PFS. Results: For 16 patients treated in dose escalation cohorts (≤10 mpk), the median age was 65 years with 31% receiving &gt;3 prior lines of therapies, and 31% progressed from immuno-oncology (IO) therapy. ADG126 was well-tolerated with no DLTs observed, nor was the MTD reached. Only Grade 1 TRAEs were reported, with fatigue (19%) and pruritis (13%) being most common. Plasma PK was approximately linear with a 1.7-fold increase in the mean t 1/2z for the total drug over the intact ADG126, suggesting the activated ADG126 accumulated steadily with &gt; 2 fold accumulation at C trough during repeat dosing, resulting in saturating target engagement at 10 mpk. Stable disease was seen in 5/16 patients with 1/5 surpassing &gt; 24 weeks. One ovarian cancer, and 1 uveal melanoma patient who progressed on nivolumab/ipilimumab, showed &gt; 20% durable reductions in target lesions by CT, and increased CD8 + T cells post-dosing. In the same ovarian cancer patient, a 77% reduction in CA-125 occurred after 7 treatment cycles at 1 mpk. Conclusions: ADG126 demonstrated excellent tolerability and safety for continuous dosing beyond 4 cycles at 10 mpk and for more than 8 cycles at 1 mpk. Compared to ADG116, its non-masked parental Ab, ADG126 exhibited superior PK and early efficacy signals correlated with increased peripheral CD8 + T cells, in general. ADG126 may offer better safety and efficacy profile than ipilimumab, which could help realize the full potential of blocking the CTLA-4 pathway. Combination studies of ADG126 with anti-PD-1Ab(s) have been initiated to determine their safety and efficacy in IO-sensitive and resistant cancer types. Clinical trial information: NCT04645069.